Barium sulfate contrast media

ABSTRACT

A barium sulfate contrast medium which comprises a barium sulfate aqueous suspension having a barium sulfate concentration of 750 to 1,200 grams per liter of the suspension and containing carbon dioxide in combination with a suspending agent, said carbon dioxide being contained in the range of 0.2 to 4 gas volume.

United States Patent Kikuchi et al.

[54] BARIUM SULFATE CONTRAST MEDIA [72] Inventors: Katsumi Kikuchi; KojiDaigo, both of Sakai-shi, Japan [73] Assignee: Sakai Chemical IndustryCompany Limited, Osaka-fu, Japan 22 Filed: Sept. 9, 1968 21 Appl.No.:758,597

[45] Sept. 5, 1972 2,996,433 8/l96l l-loppe et al. ..424/S 3,218,349 1l/ 1965 Chapman et al ..424/5 3,235,462 2/ l 966 Wolfson .,424/43,236,735 2/1966 Brown ..424/4 Primary Examiner-Albert T. MeyersAssistant ExaminerFrederick E. Waddell Attorney-Larson, Taylor & Hinds[57] ABSTRACT A barium sulfate contrast medium which comprises a bariumsulfate aqueous suspension having a barium sulfate concentration of 750to 1,200 grams per liter of the suspension and containing carbon dioxidein combination with a suspending agent, said carbon dioxide beingcontained in the range of 0.2 to '4 gas volume.

9 Claims, No Drawings Barium sulfate has been used for years as acontrast medium in the form of an aqueous suspension in examination ofdigestive system. The barium sulfate contrast medium is required tohave:

1. High suspension stability to permit trouble-free storage andtransportation,

2. Higher concentration of barium sulfate to enhance contrast effect,

3. Low liquid viscosity to facilitate oral administration, and

4. Forming a smooth, continuous and uniform coating on the surface ofthe digestive canal to be examined.

The conventional barium sulfate contrast media, however, with suchuseful properties as above mentioned have not so far been provided. Forexample, barium sulfate merely suspended in water is extremely unstable,and barium sulfate settles in quite a short time. To improve thestability of the suspension, suspending agents such as sodiumcarboxymethyl cellulose, sodium alginate, gelatin, tragacanth, etc. areused. Such agents improve the stability of the suspension and lower theviscosity of the suspension. Thus, the addition of said agents improvesthe stability of the suspension but to an insufficient extent. Theincrease of the agents used increases the stability but at the same timeincreases the liquid viscosity to make the oral administrationdifficult. The trend is prominent with higher concentration of bariumsulfate. In fact when the suspension contains barium sulfate in anamount of more than 750 grams per liter of the suspension and asuspending agent in such an amount as to secure sufficient stability,the viscosity thereof is elevated to make the administration difficult.That is, in the conventional art there has been proposed no contrastmedia of high concentration with excellent stability and low viscosity.

The conventional fluoroscopy of digestive system was effected by fillingthe digestive canal with barium sulfate to which X-rays were irradiated,but in this method, when affected part is located near the edge of theimage, it can be well detected but if at the center of the image it isapt to be overlooked. To improve such drawback double contrast methodhas been proposed, in which after administrating barium sulfatesuspension, gas such as air is introduced so as to form double images ofpositive contrast medium of barium sulfate and negative medium of gas.In the above method, however, it is practically very difficult toeffectively introduce gas such as air into digestive canal after theadministration of barium sulfate. Thus, barium sulfate suspensionsuitable for double contrast photography is strongly expected to bedeveloped.

Accordingly, an object of the invention is to provide a barium sulfatecontrast medium which is stable at a concentration of as high as morethan 750 grams per liter of the suspension and has low viscosity.

Another object of the invention is to provide a barium sulfate contrastmedium which permits double contrast photography merely byadministration without subsequent introduction of gas such as airinto-digestive canal.

Still another object of the invention is to provide a barium sulfatecontrast medium which can give a smooth, continuous, and uniform coatingon the inner walls of digestive canal without forming objectionablelumps.

A further object of the invention is to provide a barium sulfatecontrast medium which is made palatable by suppressing disagreeabletaste.

The above and other objects of the invention will be apparent from thefollowing description.

The contrast medium of the invention comprises a barium sulfate aqueoussuspension having a barium sulfate concentration of 750 to 1,200 gramsper liter of the suspension and containing carbon dioxide in combinationwith a suspending agent, said carbon dioxide being contained in therange of 0.2 to 4 gas volume. The term gas volume means the volumes ofthe gas reduced to 0C. and 760 mm dissolved by one volume of thesuspension.

According to the invention the barium sulfate aqueous suspension shouldnecessarily contain carbon dioxide and a suspending agent, for which abarium sulfate suspension having high concentration but being low inviscosity, stable and suitable for administration can be obtained. Withthe suspension having such high concentration of barium sulfate andcontaining only carbon dioxide but no suspending agent, the liquidviscosity of the suspension will rise too high for oral administrationagainst the object of the invention.

The suspension of the invention is thus stable at high concentration andlow in viscosity, and further, when administered, carbon dioxidecontainedin the suspension will so expand within digestive canal thatbarium sulfate is pressed against the inner walls of the canal, thusforming a smooth, continuous and uniform coating on the surface of thecanal without allowing formation of lumps. And because of the presenceof carbon dioxide, double contrast photography of digestive systembecomes possible without introduction of the gas after administration ofthe contrast medium and gives palatable and refreshing taste inadministration just like drinking aerated water.

In the invention barium sulfate of finer grain is preferred, andgenerally barium sulfate of an average particle size of 0.02 to 2 y. maybe used, most desirable being those having an average particle size ofsmaller than 1 p" The barium sulfate is contained in the presentsuspension in such a high concentration as 750 to 1,200 grams,preferably 800 to 1,100 grams, per liter of the suspension.

The suspension of the invention should contain carbon dioxide, in therange of 0.2 m4 gas volume. If the carbon dioxide is used in excess ofthe above amount a special pressure vessel will become necessary andwhen opened for administration, the suspension will blow out, and ifless amount of the gas is used, the stability of the suspension can notbe improved sufficiently. Desirable amount of carbon dioxide is 0.4 1.2gas volume.

The conventional suspending agents, such as sodium carboxymethylcellulose, sodium alginate, gelatin, tragacanth, acacia, etc. can beused for the purpose. The amount of the suspending agent used can besuitably selected according to the kinds of the agent used, bariumsulfate concentration of the suspension,

etc. but generally it may be used in the range 0.2 10 by weight percent.Preferable amount of sodium car boxymethylcellulose and sodium alginateis 0.4 to 1.1 weight percent and that of gelatin, tragacant and acaciais l to 5 weight percent, based on the weight of the barium sulfate.

Through the researches of the inventors it was found that by adding tothe contrast medium of the invention water-soluble salts of citric acid,polyphosphoric acid and ethylenediaminetetraacetic acid, the liquidviscosity is considerably reduced without affecting the stability of thecontrast medium. There are available various water-soluble salts of saidacids, desirable being alkali metal salts such as sodium, potassium,etc.; alkali earth metal salts such as magnesium, etc.; and ammoniumsalts, etc. These salts may be either normal salts or hydrogen salts,but normal salts are preferable. Concretely, these are sodium citrate,potassium citrate, magnesium citrate, ammonium citrate, sodiumpyrophosphate, potassium pyrophosphate, sodium metaphosphate, potassiummetaphosphate, sodium ethylenediaminetetraacetate, potassiumethylenediaminetetraacetate, etc. The most desirable of these salts arewater-soluble salts of polyphosphoric acids, which not only reduce theviscosity of the suspension but also completely eliminate flocculationor coagulation occurring when barium sulfate comes in contact withgastric juice, said flocculation often leading to erroneous diagnosis.These water-soluble salts can be singly or in mixture in a range of 0.01to 2 weight percent, preferably 0.1 and 0.6 weight percent, based on theweight of the barium sulfate.

The contrast medium of the invention can be prepared, for example, byfirst dissolving in water a suspending agent, then suspending bariumsulfate in the resultant aqueous solution with stirring, placing thushomogenized mixture in a container, dissolving carbon dioxide in themixture and finally sealing the container. Carbon dioxide in an amountof only 0.2 4 gas volume will exhibit sufficient effects, so that noparticular pressure vessel is needed. Carbon dioxide can be introducedin the form of carbonated water or Dry Ice. When carbonated water isused, the homogenized mixture is placed in a container and cooled toabout 0 to C to which carbonated water cooled at the same temperature isadded and the container is sealed, and in the case of the latter, DryIce pellets can be placed in the container holding the mixture, andsealed immediately. When a water soluble salt of citric acid,polyphosphoric acid and ethylenediaminetetraacetic acid is used, it maybe first dissolved in water with a suspending agent, or may be dissolvedin water singly and after suspending barium sulfate in the solution asuspending agent is added to the homogenized mixture.

To the contrast medium of the invention can be added as desiredsweetening material, spices, antiseptic, etc. according to theconventional method.

For better understanding of the invention examples are given below.

EXAMPLE 1 In excess amount of water the predetermined amount of sodiumcarboxymethyl cellulose was dissolved, and to the solution 75 kilogramsof barium sulfate was added with stirring in amount necessary forproducing final suspension of barium sulfate concentration of 750 gramsper liter of the suspension. 50 milliliters of the resultant homogenizedmixture was placed in each tin-plated can, to which the predeterminedamount of Dry Ice was added and the can was immediately sealed.

For comparison suspensions were prepared in the similar manner as above,in which sodium carboxymethyl cellulose or carbon dioxide was not used.

For measuring the viscosity of each suspension, the respective can werecooled to 5C and the suspensions were taken out therefrom. The viscosityof the suspensions was measured by using Brookfield viscometer at 30 rpmat 5C, with the results shown in Table 1 below.

From the Table 1 above the effects of suspending agents and carbondioxide on the viscosity of the suspension will be apparent. Theaddition of about 0.2 weight percent suspending agent to the suspensionreduces the viscosity but with the addition of a larger amount of thesuspending agent it gradually increases the viscosity. The suspensioncontaining carbon dioxide but no suspending agent has markedly higherviscosity than that containing no carbon dioxide and suspending agent,and is unfit for oral administration. However, in the case of thesuspension containing both suspending agent and carbon dioxide theeffect of carbon dioxide on the viscosity of the suspension isunnoticeable and it shows almost no rise of viscosity as compared withthat containing no carbon dioxide.

EXAMPLE 2 In excess amount of water the predetermined amount of sodiumcarboxymethyl cellulose was dissolved and to the solution barium sulfatewas added with stirring in amount necessary for producing finalsuspension of barium sulfate concentration of 1,000 grams per liter ofthe suspension. 50 milliliters of the homogenized mixture thus obtainedwas placed in each SO-milliliter graduated glass cylinder, to which thepredetermined amount of Dry Ice was added and the cylinder wasimmediately plugged airtight.

For comparison suspensions were prepared in the similar manner as above,in which sodium carboxymethyl cellulose was not used.

The results of measurement of the viscosity and stability of thesuspensions prepared as above are given in the Table 2 below. Theviscosity was measured in the same manner as in Example 1, andsuspension stability was measured by leaving each cylinder to stand at5C for 5 days, and then measuring the volume of the portion turningtransparent, using the following criteria:

-II- More than 2.0 cc was transparent 1.5 2.0 cc was transparent Notransparent portion or less than 1.5 cc

TABLE 2 CMC-Na CO, (wt%) content (gas vol) viscosity Stability I58 I47I40 136 335 330 318 315 580 560 540 541 790 787 802 815 I512 I530 l5 I81509 From the above results it has been found the contrast media of theinvention containing carbon dioxide as well as the suspending agent canbe improved of its stability without the increase of viscosity.

EXAMPLE 3 In excess amount of water the predetermined amount of sodiumhexametaphosphate was dissolved and to the solution barium sulfate wasadded with stirring in amount necessary for producing final suspensionof barium sulfate concentration of 1,000 grams per liter of thesuspension. To the homogenized mixture thus obtained was added withstirring the predetermined amount of aqueous solution of sodiumcarboxymethyl cellulose, and after cooling to 5C 100 milliliters of themixture was placed in each tin-plated can, to which was added thepredetermined amount of Dry Ice and the can was immediately sealed.

The viscosity of the respective suspensions prepared as above wasmeasured in the same manner as in Exam ple l and the flocculationstability of the suspensions on artificial gastric juice is shown inTable 3 below, in which the flocculation stability was measured byadding each suspension dropwise to 10 milliliters of the artificialgastric juice shown below and the results observed with the necked eyewere determined according to the following criteria:

-I-I- Distinct flocculation was observed Slight flocculation wasobserved i No flocculation but slight changes occurred No changes wereobserved Amount necessary for making 1 liter solution Distilled waterTABLE 3 No. CMC CO, Sodium Vis- F locculation NaConhexametacosistability on (wt%) tent phosphate ty artificial (wt%)(cps) gastric juice l0 a 0.3 0 0 I27 10 b 0.3 0.5 O 128 i 10 c 0.3 l .00 130 t 14 d 0.3 0.5 0.3 69 l0 e 0.3 1.0 0.3 87 l 1 a 0.6 0 0 335 l l b0.6 0.5 O 318 i l l c 0.6 1.0 0 315 ill d 0.6 0.5 0.3 194 e 0.6 1.0 0.321 l l2 a 1.0 0 0 790 H 12 b I .0 0.5 0 792 I2 c 1.0 1.0 0 815 12 -d 1.00.5 0.3 564 i l2-e 1.0 1.0 0.3 561 i From the above test results, it wasobserved by the addition of sodium hexametaphosphate the viscosity ofthe suspension was considerably reduced to be easily administered. Itwas also seen the suspension containing the suspending agent only wasunstable to gastric juice, showing flocculation, whereas with onecontaining carbon dioxide, the stability was improved and by furtheraddition of sodium hexametaphosphate the stability on artificial gastricjuice was further improved.

This trend was also same with the suspensions containing otherwater-soluble salts of polyphosphoric acids.

EXAMPLE 4 In 53.8 liters of water 0.6 kilograms of sodium citrate wasdissolved, and to the solution kilograms of barium sulfate was addedwith stirring. To the homogenized mixture was added with stirringaqueous solution of 1.2 kilograms of sodium carboxymethyl cellulosedissolved in 24 liters of water and after cooling to 5C 100 millilitersof the mixture was placed in each tin-plated can, to which was added thepredetermined amount of Dry Ice and the can was immediately sealed.

The viscosity of the suspension was measured in same manner as inExample 1, with the results, shown in Table 4 below.

Barium sulfate suspension was prepared in the same manner as in Example4 except that 0.5 kilogram of tetrasodium ethylenediaminetetraacetatewas used in the place of sodium citrate, and 0.19 gram of Dry Ice wasused.

The suspension thus obtained was stable and had a viscosity of 260 cps.

EXAMPLE 6 Barium sulfate suspension was prepared in the same manner asin Example 4 except that 0.6 kilograms of ammonium citrate was used inthe place of sodium citrate, and 0.19 gram of Dry Ice was used.

The suspension thus obtained was stable and had a viscosity of 245 cps.

EXAMPLE 7 Barium sulfate suspension was prepared in the same manner asin Example 4 except that 0.6 kilogram of magnesium citrate was used inthe place of sodium cirate, and 0.19 gram of Dry Ice was used.

The suspension thus obtained was stable and had a viscosity of 295 cps.

What we claim is:

1. A stable aqueous barium sulfate contrast medium suspension having aviscosity suitable for oral administration comprising barium sulfate,carbon dioxide and a suspending agent selected from the group consistingof sodium carboxymethyl cellulose, sodium alginate, gelatin, tragacanthand acacia, the barium sulfate concentration being from 750 to 1,200grams per liter of medium and the carbon dioxide concentration beingfrom 0.2 to 4 gas volumes the stability of said composition beingindicated by less than 1.5 cc of said suspension turning transparentwhen 50 milliliters of said suspension is placed in an air-tightgraduated glass cylinder at C for 5 days.

2. The barium sulfate contrast medium according to claim 1, in whichsaid barium sulfate is present in the range of 800 to 1,200 grams perliter of the suspension.

3. The barium sulfate contrast medium according to claim 1, in whichsaid carbon dioxide is present in the range of 0.4 to 1.2 gas volume.

4. The barium sulfate contrast medium according to claim 1, in whichsaid suspension further contains at least one water-soluble saltselected from the group consisting of alkali metal, alkaline earth metaland ammonium salts of an acid selected from the group consisting ofpolyphosphoric acid, citric acid and ethylenediaminetetraacetic acid inthe range of 0.01 to 2 weight percent, based on the weight of the bariumsulfate.

5. The barium sulfate contrast medium according to claim 4, in whichsaid water-soluble salt is a water-soluble salt of polyphosphoric acid.

6. The barium sulfate contrast medium according to claim 5, in whichsaid water-soluble salt of polyphosphoric acid is sodiumhexametaphosphate.

7. The barium sulfate contrast medium according to claim 4, in whichsaid water-soluble salt is a water-soluble salt of citric acid.

8. The barium sulfate contrast medium according to claim 4, in whichsaid water-soluble salt is a water-soluble salt ofethylendiarninetetraacetic acid.

9. The barium sulfate contrast medium according to claim 4, in whichsaid water-soluble salt is present in the range of 0.1 to 0.6 weightpercent, based on the weight of the barium sulfate.

2. The barium sulfate contrast medium according to claim 1, in whichsaid barium sulfate is present in the range of 800 to 1,200 grams perliter of the suspension.
 3. The barium sulfate contrast medium accordingto claim 1, in which said carbon dioxide is present in the range of 0.4to 1.2 gas volume.
 4. The barium sulfate contrast medium according toclaim 1, in which said suspension further contains at least onewater-soluble salt selected from the group consisting of alkali metal,alkaline earth metal and ammonium salts of an acid selected from thegroup consisting of polyphosphoric acid, citric acid andethylenediaminetetraacetic acid in the range of 0.01 to 2 weightpercent, based on the weight of the barium sulfate.
 5. The bariumsulfate contrast medium according to claim 4, in which saidwater-soluble salt is a water-soluble salt of polyphosphoric acid. 6.The barium sulfate contrast medium according to claim 5, in which saidwater-soluble salt of Polyphosphoric acid is sodium hexametaphosphate.7. The barium sulfate contrast medium according to claim 4, in whichsaid water-soluble salt is a water-soluble salt of citric acid.
 8. Thebarium sulfate contrast medium according to claim 4, in which saidwater-soluble salt is a water-soluble salt of ethylendiaminetetraaceticacid.
 9. The barium sulfate contrast medium according to claim 4, inwhich said water-soluble salt is present in the range of 0.1 to 0.6weight percent, based on the weight of the barium sulfate.